Cancer is a serious disease that afflicts one in four people. In the last fifty years, there have been significant improvements in the early detection of cancer, as well as the development of a number of therapies to treat cancer. Therapies include surgery to remove primary tumors, and sublethal radiation and chemotherapy to treat disseminated disease. While these treatments have resulted in apparent cures for many patients, the treatments can be quite debilitating and are still often ineffective at preventing death from this disease.
Prostate cancer is the second leading cause of cancer-related death in men. Approximately 180,000 men will be diagnosed with prostate cancer each year and 40,000 succumb to the disease each year. Prostate tumor cells have a low proliferation rate and do not respond to standard chemotherapies, which are most toxic to the most rapidly dividing cells in the body. Instead, prostate cancer can be treated surgically, with radiation therapy or hormonal therapy. Surgery and radiation therapy can lead to undesirable side effects, such as incontinence and impotence. The disease can often be successfully managed with hormonal therapy, which starves the tumor cells for required growth factors. However, eventually all tumors treated in this way become androgen-independent and there is no effective treatment beyond that point.
Treatment of cancer with active immunotherapy has shown promise in many preclinical models, and in a few clinical trials as an alternative or adjunct to surgery, radiation or chemotherapy. The goal of active immunotherapy is to create a therapeutic immune response against tumor-specific antigens, which then targets tumor cells for destruction. However, most tumor antigens are self-antigens, to which the patient is tolerant. Indeed, central and peripheral tolerance mechanisms are expected to hamper the generation of effective immunity against tumors that express self-antigens.
One way to solve the problem of how to break tolerance against a given self-antigen is to use a closely related gene or protein from a different species as an immunogen. This type of immunization is also known as xenogeneic immunization and its potency lies in either the random creation of heteroclitic epitopes in the xenogeneic sequences with enhanced binding capacity to MHC class I antigens and/or the presence of strong helper epitopes within the xenogeneic sequence. For example, injection of plasmid DNA encoding a xenogeneic differentiation antigen is a powerful means to induce antibody and T-cell responses to otherwise poorly immunogenic self-antigens. This xenogeneic approach has been shown to work for a variety of cancer models using mouse or rat sequences by inducing active immunity to several different types of genes, including angiogenesis genes (Liu et al., Blood 102:1815-23, 2003), membrane glycoproteins (Wolchok et al., Cancer Immun. 1, 9-18 (2001); Sioud and Sorensen D., Eur. J. Immunol. 33, 38-45 (2003)), and integrins (Lou et al., Immunol. Invest. 31, 51-69 (2002)).
Prostate tumors and some breast malignancies express prostate specific antigen (PSA), also known as kallikrein 3 (KLK3), on their surface. PSA is well known as a serum marker for prostate cancer; increasing serum levels of PSA typically correlate well with the severity of the disease. It is unclear if PSA has a role in the etiology of prostate cancer; various reports have indicated that PSA could either enhance or inhibit tumorigenicity. Several cytotoxic T-lymphocyte (CTL) epitopes for PSA have been described for the HLA A2 and A3 haplotypes; identification of these epitopes support the possibility of generating therapeutic in vivo CTL by vaccination.
In fact, use of DNA encoding human and mouse prostate-specific membrane antigen (PSMA) has been tested in phase I clinical trials in patients with recurrent prostate cancer. See Wolchok et al., Semin. Oncol. 30, 659-66 (2003). These authors have also shown in pre-clinical studies that use of xenogeneic DNA (e.g., injection of human PSMA DNA into mice) is an absolute requirement to overcome immunologic tolerance. However, a need still exists to improve current vaccine strategies by treating human disease with a more closely related PSA antigen to stimulate anti-PSA immunity by xenogeneic immunization.